Obinutuzumab Receives FDA Approval for Follicular Lymphoma

Sandra Horning, MD

Sandra Horning, MD

Patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen, will have a new treatment option, following the FDA’s approval of obinutuzumab (Gazyva). The agency approved the anti-CD20 agent for use in combination with bendamustine followed by obinutuzumab monotherapy.

Obinutuzumab was previously approved for use in combination with chlorambucil in patients with previously untreated chronic lymphocytic leukemia.

The approval in the follicular lymphoma setting is based on findings from the phase III GADOLIN study, in which obinutuzumab plus bendamustine followed by single-agent obinutuzumab reduced the risk of disease progression by 52% compared with bendamustine alone (HR, 0.48; 95% CI 0.34-0.68; P <.0001) in patients with follicular lymphoma who progressed on rituximab (Rituxan)-based therapy.

FDA reported that the recommended dose and schedule for the regimen is obinutuzumab: 1000 mg by IV infusion on days 1, 8 and 15 of cycle 1; on day 1 of cycles 2-6 (28-day cycles); and then every 2 months for 2 years, and bendamustine 90 mg/m² by IV infusion on days 1 and 2 of cycles 1-6.

"People with follicular lymphoma whose disease returns or worsens despite treatment with a Rituxan-containing regimen need more options because the disease becomes more difficult to treat each time it comes back," said Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech. "Gazyva plus bendamustine provides a new treatment option that can be used after relapse to significantly reduce the risk of progression or death."

The multicenter, open-label, phase III GADOLIN study involved 413 patients with rituximab-refractory indolent non-Hodgkin lymphoma, the most common being follicular lymphoma (n = 321). Patients were considered rituximab-refractory if they did not respond to either rituximab monotherapy or rituximab in combination with chemotherapy, or had relapsed within 6 months of completion of the last dose of a rituximab-based regimen (rituximab monotherapy or rituximab + chemotherapy).

Patients in the experimental arm (n = 155) received bendamustine (90 mg/m² IV on days 2 and 3 of cycle 1, and days 1 and 2 of cycles 2-6) plus 6 cycles of obinutuzumab (1000 mg IV on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-6) followed by obinutuzumab every 2 months until disease progression for a maximum of 2 years. In the comparator group (n = 166), patients received 6 cycles of bendamustine monotherapy (120 mg/m2 IV on days 1 and 2 of cycles 1-6). The cycle length for both treatment arms was 28 days.

Clinical characteristics across both arms of the study were comparable: median patient age was 63 years, with a median of 2 prior lines of therapy (range, 1-10); approximately 4 months had elapsed since their last treatment. More than 90% of patients in each arm were refractory to their last treatment.

The primary endpoint of the study was progression-free survival (PFS). Secondary outcome measures included overall survival (OS), response, and safety.

The median PFS, as determined by an independent panel, was not reached in the obinutuzumab arm versus 13.8 months in the control arm. By investigator assessment, the median PFS with obinutuzumab was 29.2 months versus 13.7 months with bendamustine alone (HR, 0.48; 95% CI, 0.35-0.67, P <.0001).

At a median follow-up of 24.1 months, the risk of death was reduced by 38% with the obinutuzumab regimen, compared with bendamustine alone (HR, 0.62, 95% CI, 0.39-0.98), according to Genentech. Neither study arm has reached median OS.

The best overall response (BOR) rate for the obinutuzumab cohort was 78.7%, including complete (CR) and partial response (PR) rates of 15.5% and 63.2%, respectively. The BOR was 74.7% for the control arm, with a CR rate of 18.7% and a PR rate of 56%. The median duration of response was not reached for the obinutuzumab arm versus 11.6 months with bendamustine alone.

The most frequently reported adverse events (AEs) in the obinutuzumab arm were infusion reactions (69%), low white blood cell counts (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), low platelet counts (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), low red blood cell counts (12%), general weakness (11%) and urinary tract infection (10%).

Low white blood cell counts (33%), infusion reactions (11%), and low platelet counts (10%), were the most common grade 3/4 AEs observed in patients receiving obinutuzumab.

The most common serious AEs (>2%) included febrile neutropenia, neutropenia, infusion related reactions, sepsis, pneumonia and pyrexia.